1 research outputs found
Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer’s Disease Amyloid‑β Peptide Which Exhibit Reduced Neurotoxicity
Alzheimer’s disease is characterized
by deposition of the
amyloid β-peptide (Aβ) in brain tissue of affected individuals.
In recent years, many potential lead structures have been suggested
that can potentially be used for diagnosis and therapy. However, the
mode of action of these compounds is so far not understood. Among
these small molecules, the nonsteroidal anti-inflammatory drug (NSAID)
sulindac sulfide received
a lot of attention. In this manuscript, we characterize the interaction
between the monomeric Aβ peptide and the NSAID sulindac sulfide.
We find that sulindac sulfide efficiently depletes the pool of toxic
oligomers by enhancing the rate of fibril formation. <i>In vitro</i>, sulindac sulfide forms colloidal particles which catalyze the formation
of fibrils. Aggregation is immediate, presumably by perturbing the
supersaturated Aβ solution. We find that sulindac sulfide induced
Aβ aggregates are structurally homogeneous. The C-terminal part
of the peptide adopts a β-sheet structure, whereas the N-terminus
is disordered. The salt bridge between D23 and K28 is present, similar
as in wild type fibril structures. <sup>13</sup>C–<sup>19</sup>F transferred echo double resonance experiments suggest that sulindac
sulfide colocalizes with the Aβ peptide in the aggregate